PROJECT SUMMARY Project 3 Recent epidemiological studies demonstrate that the metabolic syndrome and its clinical components, obesity, hypertension, dyslipidemia, and impaired glucose tolerance, are common and strongly associated with cardiovascular disease (CVD), diabetes, and other diseases. It would be clinically significant to elucidate genetic factors that contribute to their high prevalence and population-specific differences. Large scale genome-wide association studies (GWAS) have successfully identified common and rare variants for the metabolic syndrome traits, however, the identified variants do not explain a majority of variance in these traits. Furthermore, most of the previous GWAS of CVD have been performed in Europeans, and less is known about the genomic architecture of the metabolic CVD traits in the rapidly growing Hispanic minority of the U.S. who display a high predisposition. We propose two Specific Aims that will utilize comprehensive genomic approaches and refined clinical data available in the Finnish and Mexican cohorts combined with the established synergic, interdisciplinary genomics and functional expertise of lipids and CVD that the PIs and investigators of this PPG grant possess to tackle the key challenge and scientific knowledge gap of human genetics: the slow conversion of the genome-wide associations into mechanistic insights and ethnicity-aware clinical applications. Project 3 puts heavy emphasis on investigation of human adipose transcriptome, because adipose is an accessible key tissue for obesity and other metabolic syndrome traits. In Specific Aim 1, to identify genetic regulators of the metabolic syndrome and its component traits in human adipose tissue, we propose a targeted design, focusing on the investigation of 1) the Kruppel-like factor 14 (KLF14) gene as a replicated master regulator of multiple critical metabolic genes; 2) variant-specific regulation of the lipid and obesity GWAS loci; and 3) context-specific genomic regulation of the metabolic syndrome and its obesogenic component traits. In Specific Aim 2, we aim to identify genetic and epigenetic mechanisms underlying two-way conversions between weight loss and gain in both Europeans and Latinos. Personalized medicine cannot be implemented successfully without taking into account ethnicity, making the discovery of population-specific genetic differences critically important in assessing CVD susceptibility. Accomplishing these Specific Aims will shed light on the genetic and epigenetic mechanisms underlying key risk factors of CVD in Mexicans and Europeans.